ANNUAL REPORT 2016 NATIONAL CENTRE FOR ADVERSE DRUG REACTIONS MONITORING,

NATIONAL PHARMACEUTICAL REGULATORY AGENCY (NPRA)

MALAYSIAN ADVERSE DRUG REACTIONS ADVISORY COMMITTEE (MADRAC) MADRAC was established in 1987 under the Drug Control Authority (DCA) to perform the function of monitoring safety profiles of drugs registered for use in Malaysia. MADRAC members for the 2016-2018 session comprise of Ministry of Health consultants from various specialties (including two new diciplines added this session: cardiology and oncology), pharmacists, academicians from local universities, and representatives from professional bodies. During MADRAC meetings held once in two months, causality verification is done for all local ADR reports, and all pertinent drug safety issues are discussed to provide DCA with information and recommendations if required. A total of six (6) MADRAC meetings were held in 2016, with 9,136 adverse drug reaction (ADR) reports presented for verification of causality.

Table 1: List of MADRAC Members (Jan- Dec 2016)

No. Name and Designation

Ex-officio

1 Chairman

En. Tan Ann Ling/

Dr. Salmah binti Bahri

Director of NPRA

2 Secretary

Pn. Wan Mohaina binti Wan Mohammad

Deputy Director, Centre for Post-Registration of Products and Cosmetic Control, NPRA

3 Pn. Anis Talib/

Datin Dr. Faridah Aryani bt. Md. Yusof

Secretary of the Drug Control Authority

Committee Members (Alternate Members)

1 Dr. G.R. Letchuman Ramanathan

National Head of Internal Medicine Services

Senior Medical Consultant (Endocrinology)

Hospital Raja Permaisuri Bainun, Ipoh.

(Datuk Dr. Noel Thomas Ross)

2 Dato’ Dr. Gun Suk Chyn

Head of Department and Senior Medical Consultant (Rheumatology)

Hospital Tuanku Ja’afar.

(Dato’ Dr. Azmillah Rosman)

3 Dato’ Dr. Noor Zalmy Azizan binti Mohd. Ali Azizan

Senior Consultant Dermatologist,

Hospital Kuala Lumpur.

(Dr. Rohna Ridzwan)

No. Name and Designation

4 Dr. Norzila Mohamed Zainudin

Senior Consultant Paediatrician, Hospital Kuala Lumpur.

(Dr. Tan Kah Kee)

5 Dr. Sunita Bavanandan

Consultant Nephrologist, Hospital Kuala Lumpur.

(Dr Suryati Yakob)

5 Dr. Ramli Ali Consultant Psychiatrist, Hospital Kuala Lumpur.

(Dr. Uma Visvalingam)

6 Dr. Mohd. Sapawi bin Mohamed Consultant Cardiologist, Hospital Raja Perempuan Zainab II.

(Dr. Siti Khairani binti Zainal Abidin)

7 Dr. Voon Pei Jye Medical Oncologist, Hospital Umum Sarawak.

(Dr. Ibtisam binti Muhamad Nor)

8 Dr. Rohani Jahis

Senior Principal Assistant Director,

Vaccine Prevention/ Food & Water Borne Disease Sector

Disease Control Division

Ministry of Health Malaysia

(Dr. Faridah Kusnin)

9 Prof. Datin Dr. Zoriah binti Aziz

Head of Pharmacy Department, Medical Faculty, Universiti Malaya.

(Dr. Adliah Mhd. Ali)

10 Pn. Noraini binti Mohamad

Ketua Penolong Pengarah Kanan U54,

Cawangan Klinikal dan Teknikal,

Bahagian Perkhidmatan Farmasi.

(Pn. Rosliza Lajis)

11 Dr. Thirunavukarasu s/o Rajoo

Malaysian Medical Association (MMA)

(Dr. Sivanaesan Letchumanan)

12 Dr. Steven Chow

Federation of Private Medical Practitioners’ Association Malaysia (FPMPAM)

(Dr. G. Shanmuganathan)

13 Ms. Eliza Basir

Association of Private Hospitals of Malaysia (APHM)

(Ms. Lee Seng Dee)

14 En. Wan Mohd. Hamidi

Malaysian Pharmaceutical Society (MPS)

(En. Lee Min Shen)

ANALYSIS OF ADR REPORTS The National Centre received 13,789 ADR reports in 2016 (Figure 1). This figure includes Adverse Events Following Immunisation (AEFI) reports received by NPRA. Detailed analysis of the ADR reports received in 2016 is shown in Figures 2 to 7.

STRENGTHENING THE PHARMACOVIGILANCE OF VACCINES

The NPRA received 954 Adverse Events Following Immunisation (AEFI) reports in 2016, 656 (68.8%) involving the Human Papilloma Virus (HPV) vaccine. Active surveillance is conducted for this vaccine since it was introduced into the National Immunisation Programme in 2010. The majority of the adverse events reported via this active surveillance programme have been non-serious, and HPV vaccination in Malaysia continues to be a safe programme for prevention of cervical cancer. Vaccine Safety Expert Group The Vaccine Safety Expert Group (JPKV) was established in February 2016. The role of this group is to make the final decision regarding the causal relationship between a vaccine and serious AEFI cases which require further discussion. Vaccine Pharmacovigilance Guidelines The second edition of the Malaysian Vaccine Pharmacovigilance Guidelines for Healthcare Professionals was released in August 2016. Key updates included revision to the investigation procedures for serious AEFI cases involving MOH and private healthcare facilities. Among the revised procedures were vaccine quarantining, vaccine handling, vaccine quality investigation, patient investigation, and investigation of vaccine storage at the immunisation facility.

Figure 1: Total Number of ADR/AEFI Reports Received in Malaysia (2007-2016)

NU

MB

ER O

F R

EPO

RT

S

Figure 2: ADR/ AEFI Reports by Category of Reporters (2010-2016)

Figure 3: ADR/ AEFI Reports by State from MOH Facilities (2016)

NU

MB

ER O

F R

EPO

RT

S

Figure 4: ADR/ AEFI Reports by Patient Age Group (2016)

Figure 5: ADR/ AEFI Reports by Patient Gender (2016)

Figure 6: Number of Adverse Drug Reactions by Pharmacological Group (2016)

Figure 7: Number of Adverse Drug Reactions by System Organ Class (2016)

SYST

EM O

RG

AN

CLA

SS

MALAYSIAN PHARMACOVIGILANCE GUIDELINES (SECOND EDITION) In September 2016, NPRA published the Malaysian Pharmacovigilance Guidelines (2nd edition) to align with current international requirements in adverse drug reaction (ADR) reporting and safety monitoring of medicinal products. This guidance document has been updated since its first publication in 2002, to include detailed information on ADR reporting for healthcare professionals and product registration holders (PRHs), as well as the responsibilities of PRHs in drug safety monitoring. CONSUMER SIDE EFFECT REPORTING FORM (ConSERF) To increase consumer empowerment, a new form for direct consumer ADR reporting (known as the Consumer Side Effect Reporting Form – ConSERF) was released in October 2016 to ensure the Malaysian ADR database captures more complete coverage of types of ADRs and products, including traditional products and health supplements. This form is available for download on the NPRA website, along with guidance for reporters.

Figure 8: New Consumer Side Effect Reporting Form – ConSERF

(a) English version

(b) Bahasa Melayu version

CPD POINTS FOR ADR REPORTING BY PHARMACISTS As part of the effort to increase the quantity and quality of ADR reports in particular from private sector healthcare professionals, beginning January 2016, pharmacists are eligible to claim Continuing Professional Development (CPD) points for the submission of quality ADR reports. The Pharmacy Board Malaysia has agreed to award one (1) CPD point under category A4 for every ADR report submitted to the NPRA which fulfills certain mandatory criteria [Ref: KKM-55/BPF/101/001/01 JLD 29 (20) and KKM.600-16/1/6(57)]. MONITORING DRUG SAFETY ISSUES In 2016, a total of 130 drug safety issue alerts were identified, mostly through the screening of reference regulatory agency alerts which is carried out daily. Following review, 25 issues were presented at MADRAC meetings to determine the appropriate risk minimisation measures [Table 1]. The majority of these issues resulted in updates to the package insert safety information, such as tightening of indications or additional contraindications. Regulatory actions for nine (9) of these issues were proposed to the DCA, resulting in DCA directives issued to ensure package inserts of all generic products containing the affected active ingredients are updated with the required safety information. Besides that, review and approval of safety-related updates to product package inserts were carried out for 336 products.

Table 1: Drug Safety Issues Discussed by MADRAC

MADRAC Recommendation/ Resulting Action

No. Product name (active ingredient) & Safety Issue

DCA Directive

PI Update

DHPC Publication of article

Further review

1 Fusafungine: Revocation of marketing authorisations for fusafungine sprays in the European Union (EU) due to the Risk of Serious Allergic Reactions including Anaphylaxis

/ /

2 Xgeva® and Prolia®

(denosumab): Clinically Significant Cases of Hypercalcaemia after Cessation of Treatment with Denosumab in Pediatric Patients

/ / /

3 Mycophenolate (mycophenolate mofetil and mycophenolic acid): Risk of teratogenic effects

/ / /

4 Saxagliptin and Alogliptin:

Risk of Heart Failure

/

5 BCR-ABL Tyrosine Kinase

Inhibitors: Risk of hepatitis B

virus (HBV) reactivation

/ / /

6 Febuxostat: Potential Risk of

Heart Failure

/

7 Viekirax® (ombitasvir/

paritaprevir/ ritonavir)

and Exviera® (dasabuvir):

Not recommended in Child-

Pugh B Patients

/ / /

8 Xalkori® (crizotinib): Inclusion

of a new warning regarding

cardiac failure

/ / /

9 Bisphosphonates

(alendronate, clodronate,

ibandronic acid, pamidronate,

risedronate, zoledronic acid):

Risk of Osteonecrosis of the

External Auditory Canal

/ / /

10 Olanzapine: Risk of Drug

Reaction with Eosinophilia

and Systemic Symptoms

(DRESS)

/ / /

MADRAC Recommendation/ Resulting Action

No. Product name (active ingredient) & Safety Issue

DCA Directive

PI Update

DHPC Publication of article

Further review

11 Interferon alfa and beta: Risk

of pulmonary arterial

hypertension

/ / /

12 Sodium Valproate: Risk of

abnormal pregnancy

outcomes

/ / /

13 Minyak Cajeput (melaleuca

leucodendran) – topical

dosage form: Risk of causing

breathing problems/

shortness of breath

/ / /

14 Carbamazepine: Information

on the importance of genetic

screening for new patients to

reduce the risk of serious

cutaneous adverse events

/

15 Infliximab: Risk of Cervical

Cancer

/

16 Adempas® (riociguat): New

contraindication in patients

with pulmonary hypertension

associated with idiopathic

interstitial pneumonia (PH-

IIP)

/ / /

17 Tarceva® (erlotinib): First-line

maintanence indication now

restricted to treatment of

patients whose tumours

harbor an EGFR-activating

mutation

/ / /

18 Invokana® (canagliflozin):

Risk of lower limb amputation

(primarily of the toe)

/ / /

19 Codeine: Update of package

inserts with safety

information on the risk of

respiratory depression

/ / /

20 Warfarin: Risk of

calciphylaxis

/ / /

21 Gabapentin: Risk of serious

breathing problems

(respiratory depression)

/

MADRAC Recommendation/ Resulting Action

No. Product name (active ingredient) & Safety Issue

DCA Directive

PI Update

DHPC Publication of article

Further review

22 Enbrel® (etanercept):

Potential harm to the

developing babies of mothers

treated with Enbrel®

/

23 Miconazole (oral gel &

injection): Risk of severe

bleeding following co-

administration of miconazole

and warfarin

/

24 Implanon NXT®

(etonogestrel): Implants have

been found rarely in the

vasculature and lung. An

update on possible risks and

complications regarding

insertion, localization,

removal and migration.

/ /

25 Zaltrap® (aflibercept): Risk of

osteonecrosis of the jaw

/

SAFETY MONITORING OF NEWLY REGISTERED PRODUCTS Newly registered products, namely New Chemical Entities (NCEs) and biologic products are required to submit Periodic Benefit-Risk Evaluation Reports/ Periodic Safety Update Reports (PBRERs/ PSURs) for the first five years post-registration. PBRERs/ PSURs contain information on the product safety profile in countries where it is registered, and any changes or new findings related to product safety. In 2016, a total of 222 PBRERs/ PSURs involving 173 products were assessed, resulting in implementation of package insert changes for 23 products (13.3%) to ensure that they contain the latest safety information. Risk management plans (RMPs) are also submitted by product registration holders to NPRA when there is any concern about a risk affecting the benefit-risk balance of a product. In 2016, a total of 40 RMPs involving 26 registered products were received and reviewed. CONSUMER MEDICATION INFORMATION LEAFLETS (RiMUPs) Since April 2011, the submission of Consumer Medication Information Leaflets (or Risalah Maklumat Ubat untuk Pengguna- RiMUP) is compulsory for products which are self-administered by consumers. RiMUPs for almost 1,300 registered products are currently available on the NPRA website for consumers and healthcare professionals to view and print out. In the year 2016, a total of 3,426 RiMUPs of registered products were reviewed, with 451 (13.2%) approved and uploaded on the NPRA website for use by consumers or healthcare professionals. The remaining RiMUPs are still under evaluation. The necessary steps will be taken to ensure more RiMUPs are available for use by all parties mentioned above.

DRUG SAFETY COMMUNICATION Effective communication is essential in pharmacovigilance, to ensure the timely and transparent sharing of medicine safety information. The NPRA released three (3) issues of the MADRAC Bulletin in 2016, as well as seven (7) issues of Reaksi Drug Safety News. Two television interviews with RTM and TV AL-Hijrah were conducted in November 2016, aiming to increase public awareness on medication safety. An electronic mailing list of healthcare professionals will be maintained in the continuous effort to ensure wider and prompt dissemination of safety information. This mailing list currently consists of more than 2,000 contacts. Further information may be obtained from the NPRA website, or by emailing queries to fv@npra.gov.my. Besides the publications, a total of 12 Direct Healthcare Professional Communications (DHPCs) were approved by the NPRA for distribution in 2016. These were issued by the product registration holders to highlight important changes in the prescribing information, safety profile or use of a product. IMPROVING THE QUALITY OF ADR REPORTS Further measures are being taken to increase the quality of ADR reports in Malaysia. With the new Pharmacovigilance system and database, as well as continuous training for reporters, it is hoped that more complete reports will be received. Over the past five years, NPRA has conducted training sessions all across Malaysia on ADR report analysis and causality assessment. In 2016, training was held in Sarawak and Terengganu, involving 80 pharmacists. Such training is in-line with the future plan for causality assessment to be done at reporter institution level, for verification by the NPRA. Besides the causality assessment training mentioned above, there were 23 training programmes conducted or presentations delivered, which involved more than 1000 MOH staff, 247 private sector healthcare professionals, and 46 international participants. These sessions aimed to increase awareness on the importance of reporting, improve the quality of ADR/ AEFI reporting, and train reporters to assess causality. TOWARDS IMPLEMENTATION OF PHARMACOVIGILANCE INSPECTION The NPRA is heading towards conducting pharmacovigilance (PV) inspection in Malaysia. PV inspection is conducted by health regulatory authorities on product registration holders to determine compliance with regulatory PV obligations. In the effort to establish a competent PV Inspectorate, NPRA PV Section staff were given an overview on this topic in August 2016 by an Expert Inspector of Good Pharmacovigilance Practice from the United Kingdom (UK) Medicines and Healthcare Products Regulatory Agency (MHRA). The PV staff received further training in November 2016, from representatives of the UK MHRA PV Information & Signal Management Unit, in a two-day course coordinated by the World Health Organisation (WHO). The next stage will be for selected staff to attend fellowship training as observers of a PV inspection in the UK, scheduled in mid-2017. The Malaysian PV Guidelines will then be updated with requirements for the PV System Master File and PV Inspection. Actual

implementation of PV Inspection in Malaysia will be carried out in stages, targeted to begin in 2018. RESEARCH COLLABORATION In 2016, a total of 11 students from local universities collaborated with the NPRA for research projects, including two (2) Masters and two (2) PhD students.